Human Discs Large is a new negative regulator of human immunodeficiency virus-1 infectivity.
Human immunodeficiency virus (HIV)-1 replication is positively or negatively regulated through multiple interactions with host cell proteins. We report here that human Discs Large (Dlg1), a scaffold protein recruited beneath the plasma membrane and involved in the assembly of multiprotein complexes, restricts HIV-1 infectivity. The endogenous Dlg1 and HIV-1 Gag polyprotein spontaneously interact in HIV-1-chronically infected T cells. Depleting endogenous Dlg1 in either adherent cells or T cells does not affect Gag maturation, production, or release, but it enhances the infectivity of progeny viruses five- to sixfold. Conversely, overexpression of Dlg1 reduces virus infectivity by approximately 80%. Higher virus infectivity upon Dlg1 depletion correlates with increased Env content in cells and virions, whereas the amount of virus-associated Gag or genomic RNA remains identical. Dlg1 knockdown is also associated with the redistribution and colocalization of Gag and Env toward CD63 and CD82 positive vesicle-like structures, including structures that seem to still be connected to the plasma membrane. This study identifies both a new negative regulator that targets the very late steps of the HIV-1 life cycle, and an assembly pathway that optimizes HIV-1 infectivity.
Perugi
Fabien
F
Department of Cell Biology, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale, Paris, France.
Muriaux
Delphine
D
Ramirez
Bertha Cecilia
BC
Chabani
Sabah
S
Decroly
Etienne
E
Darlix
Jean-Luc
JL
Blot
Vincent
V
Pique
Claudine
C
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D000074288:Discs Large Homolog 1 Protein; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D006801:Humans; D051861:Kangai-1 Protein / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D060149:Tetraspanin 30; D014771:Virion / Q000235:genetics / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C554586:CD63 protein, human; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D015683:Gene Products, gag; D051861:Kangai-1 Protein; D008565:Membrane Proteins; D010980:Platelet Membrane Glycoproteins; D034741:RNA, Small Interfering; D060149:Tetraspanin 30; D054299:env Gene Products, Human Immunodeficiency Virus